Segmented PD-L1 Binding Polypeptides for Tumor Penetration
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Solution Overview
Problem
Current monoclonal antibodies targeting PD-1 and PD-L1 have low tissue penetration, leading to high doses required for cancer treatment, which increases the risk of immune-related side effects and toxicities, and there is a need for tools that can efficiently assess and target PD-L1 within tumors.
Innovation Solution
Development of polypeptides comprising immunoglobulin variable domains that specifically bind to human Programmed Death Ligand-1 (huPDL1), with selected complementarity determining regions (CDRs) for high affinity and specificity, which can be used as medicaments or diagnostic agents, including imaging agents to visualize PD-L1 expression in tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If monoclonal antibodies are administered at high doses to ensure sufficient uptake in the tumour, then tumour targeting is improved, but immune-related side effects and toxicities increase
Solution Approach 1:
The patent segments the antibody molecule into smaller format variants (nanobodies, affibodies, adnectins, peptides) that can penetrate tissue more effectively, reducing the need for high doses while maintaining tumour targeting capability
Solution Approach 2:
The patent changes the physical parameters of the targeting moiety by using smaller molecular weight formats (e.g., nanobodies of ~15 kDa vs. full antibodies of ~150 kDa), which improves tissue penetration and allows lower dosing to achieve sufficient tumour uptake
2Reliability
If monoclonal antibodies are used to target PD-L1, then therapeutic effect is improved, but tissue penetration capacity deteriorates
Solution Approach 1:
The patent divides the large monoclonal antibody into smaller modular formats including nanobodies (single domain antibodies), affibodies, adnectins, and cyclic peptides, each with reduced molecular size that enables deeper tissue penetration while preserving PD-L1 binding capability
Solution Approach 2:
The patent uses smaller protein formats and peptide intermediaries that can more easily navigate through extracellular matrix and reach intracellular PD-L1 targets, serving as effective mediators between the immune system and tumour cells
3Measurement precision
If tools are needed to assess dynamic immune checkpoint expression and target PD-L1 efficiently, then diagnostic capability is improved, but current monoclonal antibodies are too large for efficient targeting
Solution Approach 1:
The patent employs segmented, smaller-sized targeting molecules (nanobodies, affibodies, adnectins, peptides) that can efficiently reach and bind PD-L1 in tumours, enabling both precise imaging and effective therapy with reduced molecular dimensions
Solution Approach 2:
The patent utilizes detectable moieties (fluorophores, radionuclides) attached to the small targeting molecules to enable optical or nuclear imaging of PD-L1 expression, providing diagnostic capability through signal detection rather than physical size
Data Source
AI summary
The invention relates to polypeptides, in particular polypeptides comprising an immunoglobulin domain, binding to human Programmed Death Ligand-1 (huPDL1) and to applications of such polypeptides such as for use as a medicament or for use as diagnostic agent, for example as an immunotracer.